The pharmaceutical art recognizes that, when highly active medicaments are prepared in pharmaceutical form for administration to subjects in need of therapy, the even distribution of active ingredient throughout the carrier is important for insuring a proper dosage and no toxic effects due to hot spots of drug. The problem is especially applicable to low dose steroidal compounds; for example, estrogens, progestins, digitalis, spironolactone. These are known to migrate through the carrier upon drying.
The prior art of low dose pharmaceutical formulation is illustrated in the literature for estrogen (e.g., estradiol). Much of the prior art comprises broad disclosures of standard preparative methods; for example, Pasquale, U.S. Pat. No. 4,544,554, etc., or Lerner, U.S. Pat. No. 3,568,828, with no mention of the problem of non-uniform distribution. The latter reference describes the preparation of low dose drugs using conventional wet granulating methods with organic solvents such as chloroform.
DeHaan (Akzo), European Patent Application No. 92103963.2, discusses the problem of uneven distribution of low dose medicaments in solid pharmaceutical dose units. This, as stated above, may be due in part to migration of the medicament. DeHaan further states that liquid granulation methods for preparing solid dosage units of low dose medicaments are also not acceptable because of the cost and environmental handicaps of the organic solvents which are unacceptable for this use.
DeHaan suggests an alternative method of manufacture which uses the compression of a dry solid mix containing an excipient having a prescribed binding-demixing ratio of the medicament to excipient.
There remains a need in the art for other methods of preparing solid dosage forms, mainly tablets of low-dosage medicaments, which can be adapted by manufacturing pharmaceutical companies to available equipment.